Inflammatory diseases are a widespread cause of human suffering and loss of function. Additionally, the treatment of patients with these diseases represents a very large expense in terms of money, facilities and personnel. The incidence of many such diseases is expected to rise in the future as life expectancy and the median age of the population continue to increase.
Inflammatory diseases are known which affect many diverse tissues and organs in the body. Examples of diseases in which the inflammation is most apparent in the joints and related connective tissue are osteoarthritis, rheumatoid arthritis, tendonitis, bursitis, and the like. These diseases are most often treated with nonsteroidal antiinflammatory agents such as aspirin, ibuprofen, and piroxicam, or with antiinflammatory glucocorticosteroids. However, these treatments suffer either from a lack of efficacy in completely controlling the disease process, or from unacceptable toxic side effects.
Arthritis is a progressive disorder of unknown cause that principally affects the hands and large weight-bearing joints and is clinically characterized by pain, deformity, and limitation of motion. Pathologically, it is characterized by erosive lesions, cartilage destruction, subchondral sclerosis, cyst formation, and osteophytes at the joint margins. Arthritis is a potentially crippling disease that is second only to cardiovascular diseases in producing severe chronic disability (Epstein, New England J. Med. (1989) 239: 1322). It affects nearly 10 percent of the population over age 60. This high incidence rate results in billions of dollars in costs annually for medications, surgery, and lost productivity (Peyron, Clin. Orthop. (1986) 213: 13; Holbrook, Am. Acad. Orthopaedic Surgeons (1984) 1). Thus a treatment to arrest and/or reverse the progress of arthritis would be of considerable benefit to mankind.
The compounds of the present invention, 5H-[1,2]benzisothiazolo[2,3-a]quinoline-5-ones, represent a novel structural class, and no previous investigations into their preparation or antiinflammatory properties have been reported.
Welter et al., U.S. Pat. No. 4,352,799 discloses 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) as an antiinflammatory agent. ##STR1##
Welter et al., U.S. Pat. No. 4,550,168 discloses related 2-phenyl-1,2-benzisoselenazol-3(2H)-ones ##STR2## as being useful for the treatment of inflammatory diseases.
Welter et al., U.S. Pat. No. 4,397,858 discloses a series of 2-halogenophenyl-1,2-benzisothiazol-3(2H)-ones ##STR3## wherein R.sup.1 represents F, Cl, or Br, and R.sup.2 represents H, F, Cl, or Br, and claim them to be useful in the treatment of phlogistic and/or arteriosclerotic processes.
None of the references cited above disclose the compounds of the present invention or suggest that such compounds would possess activity as antiinflammatory agents or that they might be of value in the treatment of arthritis.